Progesterone antagonists such as CDB-4124 in the treatment of endometriosis, uterine fibroids, dysmenorrhea, breast cancer, etc

ABSTRACT

The present invention relates to methods of administering compositions comprising a progesterone receptor antagonist for use in treating estrogen-dependent conditions. The invention is also directed to methods for treating pain associated with endometriosis. The compositions may be administered to females with endometriosis as well as to females undergoing estrogen and/or selective estrogen receptor modulator (SERM) therapy. In certain embodiments, the invention provides a method for suppressing endometrial proliferation.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is the National Stage of InternationalApplication Number PCT/US2009/041826, filed Apr. 27, 2009, and claimsthe benefit of U.S. Provisional Patent Application No. 61/048,472, filedApr. 28, 2008, the contents of each of which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to compositions and methods for treatingan estrogen-dependent condition. More specifically, the presentinvention relates to compositions comprising one or more progesteroneantagonists for suppressing endometrial proliferation.

BACKGROUND OF THE INVENTION

Estrogens are a group of hormones essential for a variety of physiologicprocesses including the development of the uterus and breasts, themaintenance of bone density, and cardiovascular protection through itspositive effect on lipid profiles. The effects of estrogen are mediatedthrough its binding to estrogen receptors in the nucleus. According tothe classic model, unoccupied estrogen receptor in the nucleus, uponbinding estrogen, acquires the ability to interact with DNA sequenceswithin the promoters of estrogen-responsive genes. The DNA-boundestrogen receptor modulates the transcription of these genes, eitherpositively or negatively.

Estrogen is known to have a hyperproliferative effect on breast anduterine tissue. Administration of unopposed estrogen to menopausalwomen, for example, has been demonstrated to lead to both endometrialhyperplasia and endometrial cancer. In contrast, progesterone potentlycounteracts estrogen-dependent endometrial proliferation and cancerdevelopment. Therefore, to counteract the effects of unopposed estrogen,progestin is commonly prescribed as part of a hormone replacementtherapy (HRT). However, a large clinical study from the Women's HealthInitiative recently determined that the combination of conjugatedestrogen and medroxyprogesterone acetate increased the risk ofdeveloping cardiovascular disease, stroke, pulmonary embolism and breastcancer. Additionally, experimental data in macaques made surgicallymenopausal has shown that a regimen of combined estrogen andprogesterone led to higher levels of breast proliferation andhyperplasia then estrogen alone. Coadministration of progestin has alsobeen associated with break-through bleeding, further limiting itssuitability as an agent for countering the hyperproliferative effects ofestrogen.

Many compounds are known in the art which affect estrogen-dependentactivation of the estrogen receptor. Depending on a variety of factorsthese compounds may be entirely estrogenic, in that they mimic estrogen,entirely antiestrogenic, in that they block the effects of estrogen, orthey may fall somewhere in-between. Compounds which exhibit mixedestrogenic and antiestrogenic properties are termed selective estrogenreceptor modulators (SERMs). SERMs exert their estrogenic orantiestrogenic effects in a tissue-specific manner. The mechanismunderlying this tissue-specificity is not clear, but may involve, interalia, the recruitment of corepressor and coactivator proteins whoserelative expression levels vary among tissue types and tissue-specificexpression of estrogen receptor isoforms α and β. Estrogen receptor α isan activator whereas estrogen receptor β can inhibit estrogen receptor αactivity by forming a heterodimer with it.

The dual activities of SERMs provide several potential advantages towomen. The estrogenic properties of SERMs may be used to treat orprevent diseases caused by estrogen deficiency such as osteoporosis,while minimizing some of the undesirable effects of estrogen.Conversely, the antiestrogenic properties of SERMs may be used toprevent or treat diseases such as breast cancer, in which estrogenicactivity is undesirable. Nonetheless, endometrial hyperplasia has beenassociated with SERM therapy, thus limiting its usefulness.

The SERM tamoxifen, for example, has been shown to be antiestrogenic inthe breast where it blocks the proliferative effects of estrogen and hasconsequently found favor as a treatment for certain types of breastcancer. On the other hand, tamoxifen displays estrogenic effects on boneand the uterus and has been associated with an increased incidence ofendometrial hyperplasia and endometrial cancer, limiting it's usefulnessas an antiestrogen.

A preliminary study in primates appeared to indicate that antiprogestinspossess antiproliferative effects on the endometrium. However, there isconcern that long-term treatment with antiprogestins could result inendometrial hyperplasia due to the action of unopposed estrogen. Severalstudies have demonstrated increased endometrial growth in femalesundergoing long-term administration of an antiprogestin which worsenswith time. Moreover, several recent investigations in adult women haverevealed tissue abnormalities in the endometrium of women treated withantiprogestins which appears to increase the risk of, inter alia, breakthrough bleeding. These observations have discouraged the chronic use ofantiprogestins.

There remains a need for a treatment regimen suitable for long-termadministration of antiprogestins which opposes the proliferative effectsof estrogen while maintaining the beneficial effects of estrogen on thebody and which reduces or eliminates side-effects of chronicadministration.

SUMMARY OF THE INVENTION

The instant invention relates to methods of administering compositionscomprising a progesterone receptor antagonist. The progesteroneantagonist may be a pure antiprogestin or a selective progesteronereceptor modulator (SPRM). In a preferred embodiment, the progesteroneantagonist has low affinity for glucocorticoid receptor. In anotherpreferred embodiment, administration of the progesterone antagonist to afemale does not substantially lower estrogen levels of the female. Mostpreferably, the progesterone antagonist is CDB-4124.

According to the invention, the compositions are administered to afemale beginning at a point in the female's menstrual cycle which allowsthe female to undergo menstruation at the end of that cycle.Accordingly, it is preferred that the compositions be administered to afemale beginning at day 14 of the menstrual cycle or thereafter. Forexample, the compositions may be administered beginning at day 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 of the female's menstrualcycle or thereafter.

In one embodiment, administration of the compositions is such that thefemale undergoes no further menstruations during the course oftreatment. Thus, according to this embodiment, administration of thecompositions begins at a point in the female's menstrual cycle thatallows the female to undergo menstruation at the end of that cycle;however, the female undergoes no further menstruation during the courseof the treatment.

In another embodiment, administration of the compositions allows forperiodic menstruation during the course of the treatment. For example,the compositions may be administered intermittently such that thesubject undergoes menses periodically during the course of thetreatment. This approach is expected to avoid potentially adverseeffects associated with a stagnant endometrium that may accompanyextended treatment with progesterone antagonists.

The compositions may be administered to a female in order to prevent anestrogen-dependent condition in the female. Estrogen-dependentconditions that may be treated with the compositions include, withoutlimitation, endometrial proliferation or endometrial hyperplasia.

The compositions may also be administered to a female for the preventionand/or amelioration of pain associated with disorders of thereproductive tract and disorders associated with reproductive hormonefluctuations. For example, the compositions may be administered to afemale in order to prevent and/or ameliorate dyspareunia, dysmenorrhea,migraine headaches associated with the menstrual cycle, premenstrualsyndrome or pain associated with dysfunctional uterine bleeding,fibroids and/or endometriosis. In a preferred embodiment, thecompositions are administered to a female with endometriosis in order totreat the pain associated with endometriosis. In one aspect, theprogesterone antagonists are chronically administered for treating painassociated with endometriosis.

The compositions may also be administered to a female undergoingestrogen and/or SERM therapy. In one aspect, the invention providesmethods for preventing the development of endometrial hyperplasia and/orendometrial cancer in estrogen and SERM therapies.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph depicting the effect of selective progesteronereceptor modulators on serum cortisol in rats.

FIG. 2 is a graph depicting the dose-dependent effect of CDB-4124 onserum cortisol in rats.

FIG. 3 is a time-line of the female menstrual cycle. Vascularization andglandularization of the endometrium is depicted as beginning at aroundday 5 of the menstrual cycle with a dramatic increase at day 14 andthereafter under the influence of progesterone.

DETAILED DESCRIPTION OF THE INVENTION

The term “effective dosage” means an amount of the composition's activecomponent sufficient to achieve the desired effect which may be, e.g.,suppression of endometrial proliferation or treatment of pain associatedwith endometriosis.

The term “estrogen-dependent condition” includes any conditionassociated with estrogen such as, without limitation, endometrialproliferation, breakthrough bleeding, spotting and endometrial cancer.

The term “selective progesterone receptor modulators” means compoundsthat affect functions of progesterone receptor in a tissue-specificmanner. The compounds act as progesterone receptor antagonists in sometissues (for example, in the uterus) and as progesterone receptoragonists in other tissues.

The terms “treat” or “treatment” refer to both therapeutic treatment andprophylactic or preventative measures, wherein the object is to preventor slow down (lessen) an undesired physiological change or disorder. Forpurposes of the present invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease, stabilized (i.e., not worsening)state of disease, delay or slowing of disease progression, ameliorationor palliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment. Those in need of treatment include those already with thecondition or disorder as well as those prone to have the condition ordisorder or those in which the condition or disorder is to be prevented.

The term “progesterone agonist” means a compound that binds to aprogesterone receptor and mimics the action of the natural hormone.

The term “progesterone antagonist” means a compound that binds to aprogesterone receptor and inhibits the effect of progesterone.

The term “suppress” or “suppresses” or “suppressing” used herein inreference to proliferation of endometrial tissue means that mitoticproliferation of endometrial tissue is suppressed upon administration ofa progesterone antagonist relative to untreated endometrial tissue underidentical conditions and is to be distinguished from cell death via,e.g., apoptosis. The activity of a progesterone antagonist insuppressing endometrial mitotic proliferation may be tested, e.g., in auterine cell line by, e.g., comparing the incorporation ofbromodeoxyuridine (BrdU) in cells treated with a progesterone antagonistto control (untreated) cells.

The term “not substantially reduced” as used herein in reference tohormone levels in a female means that hormone levels are maintainedwithin the normal range during administration of compositions of theinvention. Thus, it is considered that some reduction in a hormone levelmay occur so long as the hormone level is maintained within the normalrange.

The term “not substantially increased” as used herein in reference tohormone levels in a female means that hormone levels are maintainedwithin the normal range during administration of compositions of theinvention. Thus, it is considered that some elevation in a hormone levelmay occur so long the hormone level is maintained within the normalrange.

The term “not substantially thickened” as used herein in reference to afemale's endometrium means that the female's endometrium does not exceed19 mm in thickness during the administration period, as measured byultrasound. Thus, it is considered that some thickening may occur duringthe administration period so long as the female's endometrium does notexceed 19 mm in thickness. Preferably, the female's endometrium is lessthan 15 mm in thickness, more preferably is less than 10 mm in thicknessand most preferably is less than 7 mm in thickness during theadministration period. The female's endometrium may thicken by less than100% relative to baseline measurements, more preferably thickens by lessthan 50% relative to baseline measurements, and most preferably thickensby less than 25% relative to baseline measurements.

The present invention relates to methods of administering compositionscomprising a progesterone antagonist, preferably at doses effective tosuppress endometrial proliferation. As discussed below, in the case of asix-month treatment regimen with CDB-4124, proliferation was suppressedto a greater degree when higher concentrations were administered.

It has been found that the progesterone antagonist CDB-4124, whenadministered for a period beginning at day 5 of a female's menstrualcycle, exhibits an inverse dose-dependency on endometrial thickness. Inother words, administration of a relatively low concentration ofCDB-4124 results in a substantial thickening of the endometrium duringtreatment. This effect is diminished when higher concentrations ofCDB-4124 are administered. The methods arise from the unexpected findingthat the development of cystic dilatation of the endometrial glands isthe principal cause of the endometrial thickening that occurs duringtreatment with CDB-4124.

If treatment is begun at a time point in the female's menstrual cyclethat does not allow for menstruation to occur at the end of that cycle(such as day 5 of the menstrual cycle), vascularization and glandularactivity of the endometrium will occur under any residual (unblocked)progesterone causing the cystic glands to inflate and resulting in athickening and hardening of the endometrium until CDB-4124concentrations have built up sufficiently to block the residualprogesterone. The thickened endometrium will be fragile and prone tobreakdown and bleed during the course of treatment. As discussed in moredetail at Example 11, relatively low concentrations of the progesteroneantagonist CDB-4124, if added early in the female's menstrual cycle,result in such a thickening of the endometrium during the course of thetreatment which can lead to bleeding.

According to the instant invention, administration of the progesteroneantagonist begins during the luteal phase of the female's menstrualcycle allowing a menstruation to occur at the end of that cycle.Consequently, a lower concentration of progesterone antagonist may beused without the thickened endometrium that occurs when administrationbegins during the follicular phase. This is possible because anyearly-forming cystic glands are shed during menstruation at which pointprogesterone antagonist concentrations have accumulated to a degreesufficient to inhibit any residual progesterone. Similar advantages areexpected for all antiprogestins, as morphological abnormalities havebeen observed for several of these compounds when administered for aperiod beginning during the follicular phase of the female's menstrualcycle.

Thus, in one aspect, the present invention provides a method fortreating an estrogen-dependent condition comprising the administrationof a composition comprising an effective amount of a progesteroneantagonist to a female for a period beginning during the luteal phase ofthe female's menstrual cycle. The luteal phase of a female's menstrualcycle begins around day 14 of the menstrual cycle. Thus, administrationof the progesterone antagonist begins at least at day 14 of themenstrual cycle. This provides the advantage of allowing the use ofrelatively low concentrations of progesterone antagonist without theaccompanying thickening of the endometrium that occurs when theadministration period begins during the follicular phase of the female'smenstrual cycle.

Methods of the invention may comprise administering a compositioncomprising an effective amount of a progesterone antagonist for anadministration period of least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31 or more days. The composition may also be administered for anadministration period of least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ormore months. The composition may also be administered for anadministration period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or moreyears. During the administration period, the composition may beadministered daily or periodically such as every other day, every othermonth, and the like. The composition may also be administeredintermittently. For example, the composition may be administered for anadministration period of 1, 2, 3, 4, 5 or more months, followed by aperiod of discontinuance, followed by an administration period of 1, 2,3, 4, 5 or more months, and so on. In all cases, the administrationperiod begins during the luteal phase of the female's menstrual cycle.

By “intermittent administration” it is meant a period of administrationof a therapeutically effective dose of progesterone antagonist, followedby a time period of discontinuance, which is then followed by anotheradministration period and so forth.

By “period of discontinuance” or “discontinuance period” it is meant adiscontinuing of the daily, weekly, monthly or therebetweenadministration of progesterone antagonist. The time period ofdiscontinuance may be longer or shorter than the administration periodbut is always longer than the dosing interval during the administrationperiod. For example, where the administration period comprises daily,weekly, or monthly dosing, the discontinuance period is at least 2 days,at least 8 days or at least 32 days, respectively. Thus, thediscontinuance period may be at least about 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32 or more days.

In one embodiment, the composition is administered intermittently suchthat the subject undergoes menses during at least one discontinuanceperiod. This approach is expected to avoid the adverse effectsassociated with a stagnant endometrium. At least one, and preferablyevery discontinuance period is of sufficient length for the subject toexperience menstruation. More preferably, the subject experiencesmenstruation during every discontinuance period. In a particularlypreferred embodiment, the composition is administered daily for anadministration period of four months, followed by a discontinuanceperiod during which the subject experiences menstruation, followed byanother administration period of four months and so on. In all cases,the administration period begins during the luteal phase of the female'smenstrual cycle.

Optionally, a gonadtropin-releasing hormone (GnRH) agonist or antagonistmay administered during the discontinuance period to hasten the sheddingand refreshing of the endometrium. Non-limiting examples of GnRHagonists include nafarelin, buserelin, leuprorelin, triptorelin,goserelin, [DLys⁶]GnRH, [DAla⁶]GnRH and the like. Non-limiting examplesof GnRH antagonists include histrelin, abarelix and those found in U.S.Pat. Nos. 4,409,208, 4,547,370, 4,565,804, 4,569,927 and 4,619,914,incorporated herein in by reference in their entirety.

Optionally, a progestin may be administered during the discontinuanceperiod in order to obtain a normal menses in the patient. Administrationof a progestin preferably results in a progesterone profile that mimicsthe natural rise and fall of progesterone levels during menstruation.Such treatment regimens are well known in the art. Administration of aprogestin during the discontinuance period may also provide oppositionto the effects of estrogen in addition to that received byadministration of the progesterone antagonist and therefore may helptreat estrogen-dependent conditions such as thickening of theendometrium. Non-limiting examples of progestins include medrogestone,medroxyprogesterone, megestrol, norethindrone, progesterone,hydroxyprogesterone, acetoxypregnenolone, allylestrenol, cyproterone,desogestrel, dimethisterone, ethisterone, ethynodiol diacetate,gestadene, lynestrenol and the like.

In one embodiment, a female patient with endometriosis is administered acomposition comprising an effective amount of a progesterone antagonistin an amount effective to suppress endometrial proliferation for aperiod beginning during the luteal phase of the female's menstrualcycle.

In a related embodiment, a composition comprising a progesteroneantagonist is administered to a female in an amount effective to treatpain associated with a disorder of the reproductive tract and/or adisorder associated with reproductive hormone fluctuations for a periodbeginning during the luteal phase of the female's menstrual cycle. Forexample, administration of the progesterone antagonist may reduce painassociated with endometrial lesions, dysfunctional uterine bleeding, andfibroids. Pain is the most prevalent and debilitating symptom ofendometriosis and is the primary indication for both medical andsurgical treatment of the disease. Pain may be manifested asdysmenorrheal, pelvic pain, back pain, abdominal pain, breast pain,dyspareunia and the like. Administration of the progesterone antagonistmay also reduce the size of endometrial lesions or uterine fibroids.Current regimens for the treatment of endometriosis include GnRHagonists which induce a state of pseudomenopause by inhibiting ovarianestrogen secretion and are therefore not useful for long-termadministration due to loss in bone density, loss of total body calciumand other osteoporosis-like side effects. Compositions of the inventionmay be administered long-term with no substantial decrease in estrogenlevels.

Use of the progesterone antagonists in treating pain arises in part fromthe unexpected finding that a preferred antiprogestin, CDB-4124, hasaffinity for and can inhibit the opiate μ receptor (MOP). The opiatereceptors reside on the surface of nerve cells or neurons and bindendogenous opioid ligands leading to the alleviation of pain. The opiateμ receptor also appears to be involved in several aspects of femalereproductive neuroendocrinology such as the control of gonadotropinrelease. The capacity of CDB-4124 to bind to and inhibit the opiate μreceptor is expected to extend to other antiprogestins of its class(i.e., those with the general formula below).

In another embodiment, the present invention provides methods oftreating an estrogen-dependent condition associated with current hormonetherapies which employ estrogenic compounds such as estrogens or SERMSby co-administering an amount of a progesterone antagonist effective tosuppress endometrial proliferation, wherein the progesterone antagonistis administered for a period beginning during the luteal phase of thefemale's menstrual cycle. Estrogen-dependent conditions associated withcurrent estrogen/SERM hormone therapies include, without limitation,endometrial hyperplasia and endometrial cancer. In this regard, theprogesterone antagonist may be administered prior to, during, orsubsequent to estrogens or SERMS as part of a combined hormone therapyregimen.

In a preferred embodiment of each method of the invention,administration of the progesterone antagonist to a female does notsubstantially reduce estrogen levels in the female. Thus the presentinvention provides an advantage over current therapies for the treatmentof endometriosis which often employ gonadotropin-releasing hormone(GnRH) agonists such as Lupron® (leuprolide acetate).

In yet another preferred embodiment of each method of the invention, theprogesterone antagonist exhibits reduced affinity for the glucocorticoidreceptor. More preferably, the binding affinity of the progesteroneantagonist for the progesterone receptor is at least 1.5 times greaterthan the binding affinity of the progesterone antagonist for theglucocorticoid receptor.

Any known progesterone antagonist with characteristics of the compoundsdescribed above can be used by an artisan practicing the instantinvention. Particularly useful compounds include those disclosed in U.S.Pat. No. 6,900,193, hereby incorporated by reference in its entirety, aswell as those disclosed in U.S. Pat. No. 6,861,415, hereby incorporatedby reference in its entirety, that are 21-substituted 19-norpregnaneswith a general formula:

wherein:X may be, for example alkyl, alkenyl, alkynyl, hydrogen, halogen,monoalkylamino or dialkylamino, such as N,N-dimethylamino;R₁ may be, for example O, NOH or NO-methyl;R₂ may be, for example hydrogen or acetyl; andR₃ may be, for example methyloxy, formyloxy, acetoxy, acyloxy, S-alkoxy,acetylthio, glycinate, vinyl ether, acetoxymethyl, methyl carbonate,halogens, methyl, hydroxy, and ethyloxy.The examples of 21-substituted 19-norpregnanes include, but are notlimited to, the following 24 compounds disclosed below.1. CDB-4247 (21-propionyloxy-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

2. CDB-4361 (21-vinyl ether-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

3. CDB-4059 (21-acetoxy-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

4. CDB-4124 (21-methoxy-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

5. CDB-4031 (21-bromine-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

6. CDB-3876 (21-chlorine-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

7. CDB-4058 (21-flourine-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

8. CDB-4030 (21-methyl-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

9. CDB-4152 (21-hydroxy-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

10. CDB-4167 (21-ethyloxy-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

11. CDB-4101 (21-methoxythio-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

12. CDB-4110 (21-acetonide-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

13. CDB-4111 (21-BMD-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

14. CDB-4125 (21-(Cyp*-hydroxy)-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

15. CDB-4205 (3-hydroxyamino-21-methoxy-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

16. CDB-4206 (3-hydroxyamino-21-acetoxy-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

17. CDB-4226 (3-hydroxyamino-21-ethyloxy-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

18. CDB-4262 (3-methoxyamino-21-ethyloxy-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

19. CDB-4223 (21-methylthio-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

20. CDB-4119 (4-benzoin-21-acetylthio-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

21. CDB-4239 (4-benzoin-21-methoxy-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

22. CDB-4306 (21-glycinate-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

23. CDB-4352 (21-cyanothio-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19 norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

24. CDB-4362 (21-methoxyacetyl-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) with thefollowing structural formula:

11β-monodemethylated derivatives of the 24 compounds disclosed above(i.e., those in which X is N-methylamino) are also particularly usefulin practicing the instant invention. In this regard, CDB-4453(21-methoxy-17α-acetoxy-11β-(4-N-methylaminophenyl)-19-norpregna-4,9-diene-3,20-dione),a monodemethylated derivative of CDB-4124, has been demonstrated topossess even lower anti-glucocorticoid activity than its parent. Attardiet al., 2002, Mol. Cell. Endocrin. 188:111-123, the contents of whichare incorporated herein by reference.

Although compounds of the general formula above and theirmonodemethylated derivatives are preferred, any progesterone antagonistmay be used in the practice of the present invention for its antagonisteffect on the progesterone receptor. Preferably, the progesteroneantagonist has one or more of the following characteristics: lowantiglucocorticoid activity, minimal estrogenic and anti-estrogenicactivities, and does not substantially elevate progesterone levels.

Antiprogestins which may be useful in the invention include, withoutlimitation, asoprisnil (benzaldehyde,4-[(11β,17β)-17-methoxy-17-(methoxymethyl)-3-oxoestra-4,9-dien-11-yl]-1-(E)-oxim;J867), its metabolite J912(4-[17β-Hydroxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyd-(1E)-oxim),and other compounds described in DE 43 32 283 and DE 43 32 284; CDB-2914(17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-dien-3,20-dione)and other compounds described in Stratton et al., 2000, Hu. Reprod.15:1092-1099; JNJ-1250132 and other compounds described in Allan et al.,2006, Steroids 71:949-954; 5-Aryl-1,2-dihydrochromeno[3,4-f]quinolinesdescribed in Zhi et al., 1998, J. Med. Chem. 41:291-302;1,4-dihydro-benzo[d][1,3]oxazin-2-ones described in U.S. Pat. Nos.6,509,334, 6,566,358 and 6,713,478 to Zhang et al.;1,3-dihydro-indol-2-ones described in U.S. Pat. No. 6,391,907 to Fensomeet al.; 2,3-dihydro-1H-indoles described in U.S. Pat. No. 6,417,214 toUlrich et al.; benzimidazolones and analogues thereof described in U.S.Pat. No. 6,380,235 to Zhang et al.; 2,1-benzisothiazoline 2,2-dioxidesdescribed in U.S. Pat. No. 6,339,098 to Collins et al.; cyclocarbamatesand cyclo-amides described in U.S. Pat. Nos. 6,306,851 and 6,441,019 toSantilli et al.; cyclic urea and cyclic amide derivatives described inU.S. Pat. No. 6,369,056 to Zhang et al.; and quinazolinone andbenzoxazine derivatives described in U.S. Pat. No. 6,358,948 to Zhang etal.

Other antiprogestins that may be useful in the invention include,without limitation,(6α,11β,17β)-1′-(4-dimethylaminophenyl)-6-methyl-4′,5′-dihydrospiro[estra-4,9-diene-17,2′(3′H)-furan]-3-one(ORG-31710) and other compounds described in U.S. Pat. No. 4,871,724;(11β,17α)-11-(4-acetylphenyl)-17,23-epoxy-19,24-dinorchola-4,9,20-trien-3-one(ORG-33628);(7β,11β,17β-11-(4-dimethylaminophenyl-7-methyl]-4′,5′-dihydrospiro[estra-4,9-diene-17,2′(3′H)-furan]-3-one(ORG-31806) and other compounds described in U.S. Pat. No. 4,921,845;ZK-112993 and other compounds described in Michna et al., 1992, J.Steroid Biochem. Molec. Biol. 41:339-348; ORG-31376; ORG-33245;ORG-31167; ORG-31343; RU-2992; RU-1479; RU-25056; RU-49295; RU-46556;RU-26819; LG1127; LG120753; LG120830; LG1447; LG121046; CGP-19984A;RTI-3021-012; RTI-3021-022; RTI-3021-020; RWJ-25333; ZK-136796;ZK-114043; ZK-230211; ZK-136798; ZK-98229; ZK-98734; and ZK-137316.

Still other antiprogestins that may be useful in the invention include,without limitation, mifepristone(11β-[p-(Dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one;RU 486) and other compounds described in U.S. Pat. Nos. 4,386,085,4,447,424, 4,519,946 and 4,634,695; the phosphorus-containing 17β-sidechain mifepristone analogues described in Jiang et al., 2006, Steroids71:949-954; onapristone(11β-[p-(dimethylamino)phenyl]-17α-hydroxy-17-(3-hydroxypropyl)-13α-estra-4,9-dien-3-one)and other compounds described in U.S. Pat. No. 4,780,461; lilopristone(((Z)-11β-[(4-dimethylamino)phenyl]-17β-hydroxy-17α-(3-hydroxy-1-propenyl)estra-4,9-dien-3-one)and other compounds described in U.S. Pat. No. 4,609,651; the11β-substituted 19-norsteroids, such as11β-(4-Methoxyphenyl)-17β-hydroxy-17α-ethynyl-4,9-estradien-3-onedescribed in Belagner et al., 1981, Steroids 37:361-382; the11β-aryl-4-estrenes such as(Z)-11β-[(4-Dimethylamino)phenyl)]-17β-hydroxy-17α-(3-hydroxy-1-propenyl)estr-4-en-3-onedescribed in U.S. Pat. No. 5,728,689; the 11β-aryl-estrene derivativesdescribed in U.S. Pat. Nos. 5,843,933 and 5,843,931; the11-benzaldoxime-estra-diene derivatives such as4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1-(E)-oximedescribed in U.S. Pat. No. 5,693,628; the11-benzaldoxime-17β-methoxy-17α-methoxymethyl-estradiene derivativessuch as4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1-(E)-[O-(ethylamino)carbonyl]oximedescribed in U.S. Pat. No. 5,576,310; the 5-substituted11β-benzadoxime-estra-4,9-diene-carbonic acid thiolesters such as4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1-(E)-[O-(ethylthio)carbonyl]oxime,described in WO 99/45023; the steroid esters such as(Z)-6′-(4-cyanophenyl)-9,11α-dihydro-17β-hydroxy-17α-[4-(1-oxo-3-methylbutoxy)-1-butenyl]4′H-naphtho[3′,2′,1′;10,9,11]estr-4-en-3-onedescribed in DE 19652408, DE 443-4488, DE 4216003, DE 4216004 and WO98/24803; the fluorinated 17α-alkyl chain steroids such as11β-(4-acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-3-onedescribed in WO 98/34947; the 17-spirofuran-3′-ylidene steroids such as11beta-(4-Acetylphenyl)-19,24-dinor-17,23-epoxy-17alpha-chola-4,9,20-trien-3-onedescribed in U.S. Pat. No. 5,292,878;(Z)-11beta,19-[4-(3-Pyridinyl)-o-phenylene]-17beta-hydroxy-17α-[3-hydroxy-1-propenyl]-4-androsten-3-oneand other compounds described in U.S. Pat. No. 5,439,913; the13-alkyl-11-beta-phenyl gonanes such as11beta-[4-(1-methylethenyl)phenyl]-17α-hydroxy-17beta-(3-hydroxypropyl)-13α-estra-4,9-dien-3-onedescribed in U.S. Pat. No. 5,446,036; the 11-arylsteroids such as4′,5′-Dihydro-11beta-[4-(dimethylamino)phenyl]-6beta-methylspiro[estra-4,9-dien-17beta,2′(3′H)-furan]-3-onedescribed in U.S. Pat. No. 4,921,845; the 11-beta-aryl-estradienesdescribed in U.S. Pat. Nos. 4,829,060, 4,814,327 and 5,089,488; the11-beta-aryl-4,9 gonadiens and 11-beta-aryl-13-alkyl-4,9-gonadiensdescribed in U.S. Pat. Nos. 5,739,125, 5,407,928 and 5,273,971; the11-beta-aryl-6-alkyl (or alkenyl or alkinyl) steroids described in EP289073; the 10-beta,11-beta-bridged steroids described in U.S. Pat. No.5,093,507; the 11-beta-aryl-14-beta-steroids described in U.S. Pat. No.5,244,886; the 19,11-beta-bridged steroids described in U.S. Pat. Nos.5,095,129, 5,446,178, 5,478,956 and 5,232,915; the 1-arylsulphonyl,arylcarbonyl and 1-arylphosphonyl-3-phenyl-1,4,5,6-tetrahydropyridazinesdescribed in U.S. Pat. No. 5,684,151; the 1-arylsulphonyl, arylcarbonyland arylthiocarbonyl pyridazino derivatives described in U.S. Pat. No.5,753,655; the 1,2-dihydro-[1,2-g]quinoline derivatives and1,2-dihydro-chromeno-[3,4-f]quinoline derivatives described in U.S. Pat.Nos. 5,688,808, 5,693,646, 5,693,647, 5,696,127, 5,696,130 and5,696,133; the oxa-steroids 6 derived from(8S,13S,14R)-7-oxa-estra-4,9-diene-3,17-dione 1 described in Kang etal., 2007, Bioorg. Med. Chem. Lett. 15:907-910; and the 7-oxa-steroids 4described in Kang et al., 2007, Bioorg. Med. Chem. Lett. 17:2531-2534.

In the preferred embodiment, the progesterone antagonist is theantiprogestin/SPRM CDB-4124 (21-methoxy-17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione). Example 10demonstrates that when administered to adult females for a periodbeginning at day 5 of the females' menstrual cycle, CDB-4124 at lowerdosages (25 mg/day and 12.5 mg/day) causes a thickening of theendometrium that is not observed at high dosages (50 mg/day).

Progesterone antagonist compositions of the instant invention may begiven to patients undergoing any hormone therapy associated with anincreased risk or incidence of endometrial hyperplasia or endometrialcancer. These treatments may include, but are not limited to, theadministration of estrogens or the administration of SERMs. Progesteroneantagonist compositions of the instant invention can be also given topatients undergoing antiestrogenic treatments because the patients maybenefit from antiproliferative effects that progesterone antagonistcompounds exert in endometrial tissue of the uterus.

SERMs are currently administered to treat various disorders includingbreast cancer, osteoporosis, colon cancer, neurodegenerative diseasessuch as Parkinson and Alzheimer, cardiovascular disease, vaginal atrophyand obesity. However, SERM therapy is associated with endometrialhyperplasia and endometrial cancer. For example, Tamoxifen treatment ofbreast cancer results in about a 20% incidence of hyperplasia withatypia in women with intact uteri. Patients with endometrial specimensdisplaying atypia have a 25% likelihood of progressing to carcinoma.Compounds of the present invention are administered at doses sufficientto oppose the hyperplasia that accompanies treatment with SERMs. Thecompounds of the present invention may be administered in combinationwith SERMs for the treatment of any of the aforementioned disorders.

The compounds disclosed in the instant invention may act as progesteroneantagonists in the uterus. The compounds of the instant invention may besuitable for the prolonged usage required in menopausal patientsundergoing hormone replacement therapy, as for other indications. Wheresuch usage is considered, the compounds preferably have only lowglucocorticoid receptor binding activity and therefore, the compounds donot substantially interfere with functions of glucocorticoid receptor.Thus, the application of the compounds may have reduced side effects,such as mood swings, fatigue and weight loss, typically found whenantiprogestins with a high affinity for glucocorticoid receptor areused.

In another embodiment the instant invention teaches methods that can beused for identifying compounds that possess selective progesteronereceptor binding activity. These methods include receptor binding and invivo bioassays such as anti-McGinty, anti-Clauberg, glucocorticoid,estrogenic, androgenic, anti-glucocorticoid (AG), anti-estrogen, andanti-androgen activities as well as post-coital and anti-ovulatoryactivities where in the leading compounds of the instant invention areused as a reference.

In another embodiment, the instant invention teaches that the potentialSPRMs can be also analyzed for their effect on transcriptional activityin human cells. When SPRMs disclosed in the instant invention are usedas a reference, this analysis can furnish information about (1) SPRM'sinteraction with receptor, (2) interaction of the activated receptorwith other transcription factors, (3) activation of a transcriptionalcomplex at a progesterone response element (PRE); and ultimately itseffect on gene expression. In these experiments, plasmid expressing thehPR-B can be cotransfected with any reporter known to a person skilledin the relevant art under the PRE-dependent promoter into HeLa, HepG2 orT47D cells. The reporters may include, but are not limited to,luciferase, beta-galactosidase, green fluorescent protein, redfluorescent protein or yellow fluorescent protein. After transfection,the cells are treated with either a test compound or one of thedisclosed in this application SPRMs that serves as a positive control.Following treatment, cells are assayed for reporter expression.

In another embodiment, the instant invention teaches that prospectiveSPRMs can be tested for their ability to oppose dexamethasone-inducedcell death in human lymphocytic cell line CEM-7 and compared to effectsof SPRMs disclosed in the instant specification. In these experiments,dexamethasone can be added at a concentration that results in celldeath. The cells are then treated with either RU486, one of SPRMs of theinstant invention or a test compound at concentrations between 10⁻⁶ and10⁻⁸ M.

Progesterone antagonist compounds that may be used in accordance withthe present invention can be synthesized using synthetic chemistrytechniques known in the art such as those disclosed in U.S. Pat. No.6,861,415. It is to be understood that certain functional groups mayinterfere with other reactants or reagents under the reaction conditionsand therefore may need temporary protection. The use of protectinggroups is described in ‘Protective Groups in Organic Synthesis’, 2^(nd)edition, T. W. Greene & P. G. M. Wutz, Wiley-Interscience (1991).

In one embodiment, compositions of the invention comprise one or moreprogesterone antagonists or pharmaceutically acceptable salts thereof.Depending on the process conditions the salt compound obtained may beeither in neutral or salt form. Salt forms include hydrates and othersolvates and also crystalline polymorphs. Both the free base and thesalts of these end products may be used in accordance with theinvention.

Acid addition salts may in a manner known per se be transformed into thefree base using basic agents such as alkali or by ion exchange. The freebase obtained may also form salts with organic or inorganic acids.

In the preparation of acid addition salts, preferably such acids areused which form suitably pharmaceutically acceptable salts. Examples ofsuch acids are hydrochloric acid, sulfuric acid, phosphoric acid, nitricacid, aliphatic acid, alicyclic carboxylic or sulfonic acids, such asformic acid, acetic acid, propionic acid, succinic acid, glycolic acid,lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid,glucuronic acid, fumaric acid, maleic acid, hydroxymaleic acid, pyruvicacid, aspartic acid, glutamic acid, p-hydroxybenzoic acid, embonic acid,ethanesulfonic acid, hydroxyethanesulfonic acid, phenylacetic acid,mandelic acid, alogenbensenesulfonic acid, toluenesulfonic acid,galactaric acid, galacturonic acid or naphthalenesulfonic acid. Allcrystalline form polymorphs may be used in accordance with theinvention.

Base addition salts may also be used in accordance with the inventionand may be prepared by contacting the free acid form with a sufficientamount of the desired base to produce the salt in the conventionalmanner. The free acid form may be regenerated by contacting the saltform with an acid and isolating the free acid in the conventionalmanner. Pharmaceutically acceptable base addition salts are formed withmetals or amines, such as alkali and alkali earth metals or organicamines. Examples of metals used as cations are sodium, potassium,calcium, magnesium and the like. Examples of suitable amines are aminoacids such as lysine, choline, diethanolamine, ethylenediamine,N-methylglucamine and the like

For the aforementioned purposes, the compounds of the instant inventioncan be administered to a patient via any conventional route where theprogesterone antagonist is active. For instance, a progesteroneantagonist of the instant invention can be administered orally,parenterally, sublingually, transdermally, rectally, transmucosally,topically, via inhalation, via buccal administration, or combinationsthereof. Parenteral administration includes, but is not limited to,intravenous, intraarterial, intraperitoneal, subcutaneous,intramuscular, intrathecal, intraarticular, intracisternal andintraventricular. The administration form can be a tablet, capsule,pill, nasal mist, aerosol, pellet, implant (or other depot) and thelike.

A therapeutically effective amount of the composition required for usein therapy may vary depending on the particular compound employed, themode of administration, the severity of the condition being treated, thelength of time that activity is desired, among other factors, and isultimately determined by the attendant physician. In most cases, aneffective dosage of a particular compound is one that is sufficient tosuppress endometrial proliferation. However, in general, doses employedfor human treatment typically are in the range of about 0.001 mg/kg toabout 500 mg/kg per day, for example about 1 μg/kg to about 1 mg/kg perday or about 1 μg/kg to about 100 μg/kg per day. For most large mammals,the total daily dosage is from about 1 to 100 mg, preferably from about2 to 80 mg. The dosage regimen may be adjusted to provide the optimaltherapeutic response. The desired dose may be conveniently administeredin a single dose, or as multiple doses administered at appropriateintervals, for example as two, three, four or more subdoses per day.

Illustratively, a composition of the invention may be administered to asubject to provide the subject with a progesterone antagonist in anamount of about 1 μg/kg to about 1 mg/kg body weight, for example about1 μg/kg, about 25 μg/kg, about 50 μg/kg, about 75 μg/kg, about 100μg/kg, about 125 μg/kg, about 150 μg/kg, about 175 μg/kg, about 200μg/kg, about 225 μg/kg, about 250 μg/kg, about 275 μg/kg, about 300μg/kg, about 325 μg/kg, about 350 μg/kg, about 375 μg/kg, about 400μg/kg, about 425 μg/kg, about 450 μg/kg, about 475 μg/kg, about 500μg/kg, about 525 μg/kg, about 550 μg/kg, about 575 μg/kg, about 600μg/kg, about 625 μg/kg, about 650 μg/kg, about 675 μg/kg, about 700μg/kg, about 725 μg/kg, about 750 μg/kg, about 775 μg/kg, about 800μg/kg, about 825 μg/kg, about 850 μg/kg, about 875 μg/kg, about 900μg/kg, about 925 μg/kg, about 950 μg/kg, about 975 μg/kg or about 1mg/kg body weight.

The compositions of the instant invention may contain from about 25 toabout 90% of the active ingredient in combination with the carrier, moreusually between about 5% and 60% by weight.

Solid carriers may include starch, lactose, dicalcium phosphate,microcrystalline cellulose, sucrose and kaolin, while liquid carriersmay include sterile water, polyethylene glycols, non-ionic surfactantsand edible oils such as corn, peanut and sesame oils, as are appropriateto the nature of the active ingredient and the particular form ofadministration desired. Flavoring agents, coloring agents, preservingagents, and antioxidants, for example, vitamin E and ascorbic acid, maybe included in preparations as well. Under ordinary conditions ofstorage and use, the preparations may contain a preservative to preventthe growth of microorganisms.

The compositions of the instant invention can be formulated into tabletsin a tablet press by using techniques well-known to an artisan skilledin the relevant field. Optionally, the active ingredients according tothe invention can also be pressed separately into two-layer tablets.According to the instant invention, tablets may include antiestrogens,estrogens or SERMs as one of the active ingredients. Compositions of theinstant invention can also be formulated as an oily solution.

Patients undergoing treatments with the compositions of the instantinvention should be monitored routinely for their serum estrogen andglucocorticoid levels.

The following non-limiting examples are provided to aid in understandingthe teachings of the instant invention.

All patents, patent applications and publications referenced herein arehereby incorporated by reference herein to the fullest extent allowedunder the law.

Example 1 Formulations of The Instant Invention Can Be Prepared AsTablets

To obtain tablets for practicing the instant invention, the followingingredients can be pressed together in a tablet press:

50.0 mg of CDB-4124 140.5 mg of lactose 69.5 mg of corn starch 2.5 mg ofpoly-N-vinylpyrrolidone 2.0 mg of aerosil 0.5 mg of magnesium stearate

To obtain two-layer tablets for practicing the instant invention, thefollowing ingredients can be pressed together in a tablet press:

20.0 mg of Tamoxifen 50.0 mg of CDB-4124 105.0 mg of lactose 40.0 mg ofcorn starch 2.5 mg of poly-N-vinylpyrrolidone 25 2.0 mg of aerosil 0.5mg of magnesium stearate

To obtain tablets containing antiestrogens for practicing the instantinvention, for example, the following ingredients can be pressedtogether in a tablet press:

10.0 mg of Raloxifene 50.0 mg of CDB-4124 125.0 mg of lactose 50.0 mg ofcorn starch 2.5 mg of poly-N-vinylpyrrolidone 25 2.0 mg of aerosil 0.5mg of magnesium stearate

To obtain oily preparations for practicing the instant invention, forexample the following ingredients can be mixed together and loaded intoampoules:

100.0 mg of CDB-4124 343.4 mg of castor oil 608.6 mg of benzyl benzoate

Example 2 Compounds of the Instant Invention May Have Only WeakAntiglucocorticoid Receptor Binding Activity

Certain antiprogestins were tested in receptor-binding assays for theirability to bind rabbit progesterone receptor (rbPR) and glucocorticoidreceptor (rbGR). Briefly, cytosol containing PR or GR were prepared inTEGMD buffer (10 mM Tris, pH 7.2, 1.5 mM EDTA, 0.2 mM sodium molybdate,10% glycerol, 1 mM DTT) from uterus or thymus, respectively, ofestradiol-primed immature rabbits. For PR binding, the cytosol wasincubated with 6 nM 1,2-[³H]progesterone (50.0 Ci/mmole) and competitorswere added at concentrations from 2 to 100 nM. For binding to GR, thecytosol was incubated with 6 nM 6,7-[³H]-dexamethasone (40 Ci/mmol) andtest compounds were added at concentrations from 20 to 100 nM. Afterovernight incubation at 4 C, bound and unbound [³H] steroids wereseparated by addition of dextran-coated charcoal and centrifugation at2100×g for 15 min at 4 C. Supernatants containing the [3H]-steroidreceptor complexes were decanted into vials containing 4 ml Optifluor(Packard Instrument Co.), vortexed, equilibrated in a liquidscintillation counter for 30 minutes and then counted for 2 minutes. TheEC₅₀ (Effective Concentration) for each standard curve and each of thecompound curves was determined by entering the counting data into a fourparameter sigmoidal computer program (RiaSmart® Immunoassay DataReduction Program, Packard Instrument Co., Meriden, Conn.). Relativebinding affinity (RBA) for each compound was calculated using thefollowing equation: EC₅₀ of standard/EC₅₀ of test compound×100. Thestandards for the PR and GR assays were unlabeled progesterone anddexamethasone, respectively. The results of these experiments aresummarized in Table 1, as a ratio of the relative binding affinities ofeach compound for the rbPR and rbGR receptors (rbPR/rbGR). Thisdifferential reflects the relative activity of a compound in a cell ortissue that possesses the two receptors and the requisitetranscriptional cofactors.

Also given in Table 1 are the relative biological activities of the samecompounds in the rabbit uterus by the anti-McGinty and anti-Claubergassays. Compound CDB-2914 (listed at the end of the Table) was used asthe control or reference compound (rabbit Biological Activity=1.00) forthese experiments because results of experiments using CDB-2914 havebeen published before (Hild-Petito et al., 1996; Passaro et al., 1997;Reel et al., 1998; Lamer et al., 2000). For the anti-McGinty test,immature female rabbits received a subcutaneous injection of 5 μgestradiol in 10% ethanol/sesame oil daily for 6 consecutive days. On day7, animals underwent sterile abdominal surgery to ligate a 3-4 cmsegment of both uterine horns. The test compound in appropriate solventwas injected intraluminally into the ligated segment of one uterine hornand vehicle alone into the other. A stimulating dose of progesterone(267 μg/day) was administered subcutaneously to each rabbit daily forthe next three days to induce endometrial proliferation. All animalswere sacrificed at day 10 for removal of the uterus where a segmentcentral to the ligatures was removed and fixed in 10% neutral bufferedformalin and submitted for histological processing. Five micron sectionsstained with hematoxylin and cosin were evaluated microscopically forthe degree of endometrial glandular proliferation. The percentinhibition of endometrial proliferation for each rabbit was calculatedand the mean of the group of five animals recorded. For theAnti-Clauberg test, immature female rabbits received a subcutaneousinjection of 5 μg estradiol in 10% ethanol/sesame oil daily for 6consecutive days. On day 7, animals received progesterone bysubcutaneous injection (160 μg/day) and the experimental compound inappropriate vehicle orally or subcutaneously for five consecutive days.One group of rabbits received progesterone only. Twenty-four hours afterthe last dose, all animals were sacrificed for removal of the uteruswhich was cleaned of all fat and connective tissue, weighed to thenearest 0.2 mg and placed in 10% neutral buffered formalin forsubsequent histological processing. Five micron sections stained withhematoxylin and eosin were evaluated microscopically for the degree ofendometrial glandular proliferation. The percent inhibition ofendometrial proliferation at each dose level of the test compound wasderived by comparison with progesterone-stimulated animals alone. Thedata presented in Table 1 (rabbit Biol. Act.) reflects the average ofthe results obtained for each compound by the anti-McGinty andanti-Clauberg assays relative to CDB-2914.

The tested antiprogestins were ranked on the basis of the selectivity ofeach compound for the rabbit PR over the rabbit GR, as listed inTable 1. The antiprogestins were also ranked on the basis of thebiological activity in the rabbit uterus. Data presented in Table 1 showthat the affinity of leading compounds for progesterone receptor was atleast 1.5 times greater than their affinity for glucocorticoid receptor.

The results of these studies also show that the two leading compoundsCDB-4124 and CDB-4059 have strong antiprogestin activity in the rabbituterus in comparison to RU 486 and CDB-2914. Both compounds lackestrogenic, androgenic, anti-estrogenic, and anti-androgenic activities.Both compounds possess minimal anti-glucocorticoid receptor activity, afeature that distinguishes them from RU 486 and CDB-2914 which aremoderately active in glucocorticoid receptor binding. In these assays,CDB-4124 performed slightly better than CDB-4059

TABLE 1 RECEPTOR BINDING AND BIOLOGICAL ACTIVITIES OF SPRMS SPRMrbPR/rbGR rabbit Biol. Act. 4239 14.80 0.60 4241 9.10 0.34 4361 7.203.03 4306 5.90 0.95 4363 5.75 2.53 3875 5.11 1.40 4362 4.74 1.25 43524.21 0.57 4176 3.83 0.20 4243 2.90 0.00 4119 2.60 0.10 4324 2.16 1.104247 2.06 1.70 4205 1.99 1.00 4059 1.89 2.90 4400 1.76 2.29 3247 1.740.10 4167 1.69 1.50 4124 1.58 3.60 4226 1.51 0.54 4206 1.44 0.68 44161.33 0.77 4417 1.31 0.70 4111 1.30 0.36 4125 1.19 1.55 4223 1.17 notgiven 4398 1.16 0.99 4058 1.08 0.90 4418 1.03 0.25 4177 1.03 0.00 40300.96 0.30 4374 0.95 2.25 4399 0.93 0.35 4152 0.82 1.40 4110 0.70 0.104031 0.69 0.70 4101 0.61 0.65 4248 0.42 0.00 4227 0.38 0.00 4393 0.350.00 4396 0.18 not given 2914 1.07 1.00

Example 3 Measuring Cortisol

Several different experimental systems support a conclusion that RU 486increases cortisol because RU 486 has strong anti-glucocorticoidproperties in humans and primates.

However, as shown in FIG. 1, rats treated with RU 486 at 10 mg/kg showedno significant difference in the levels of cortisol. In contrast, ratstreated with either CDB-4124 or CDB-4059 at the same dose levels hadsignificantly higher levels of serum cortisol than rats from a controlgroup.

These higher levels were in the range of 3-4 ug/dl (30-40 ng/ml). Theeffects were dose-dependent in that increasing doses of CDB-4124 led toincreased cortisol (FIG. 2).

This difference in effects of RU 486 versus CDB-4124 or CDB-4059 oncortisol levels can be explained by assuming that after 21 days ofchronic dosing, a rat liver was able to metabolize RU 486 better thaneither of the two CDB compounds.

Example 4 Measuring Corticosterone

Corticosterone is the most abundant glucocorticoid in rats. The effectsof the SPRMs on cortisol shown in FIGS. 1 and 2 may be secondary tostrong effects on corticosterone. To better explore this phenomenon, thelevels of corticosterone were measured in groups, which showed thestrongest changes in cortisol levels, such as groups treated withCDB-4124 at 20 mg/kg or 10 mg/kg. For comparison, the following groupswere also assayed: a group that received 20 mg/kg CDB-4124 plus 10 mg/kgprogesterone, a group that received 10 mg/kg CDB-4124 plus 10 mg/kgprogesterone, a group that received 10 mg/kg RU 486, a group thatreceived 10 mg/kg of progesterone alone, a control group. The levels ofcorticosterone were 10-40 times higher than the levels of cortisol.However, almost no difference between groups with respect to meancorticosterone levels was observed. There were no differences among thegroups before treatment (p=0.43, Kruskal-Wallis test), after 21 days oftreatment (p=0.57, Kruskal-Wallis test), or after 28 days of treatmentand at sacrifice (p=0.061, Kruskal-Wallis test.

To measure effects of exogenous progesterone on serum corticosterone,the levels of corticosterone were compared in 3 paired groups thatdiffered in whether they received exogenous progesterone (e.g.,comparisons of control versus progesterone or CDB-4124 at 20 mg/kgversus CDB-4124 at 20 mg/kg plus progesterone, or CDB-4124 at 10 mg/kgversus CDB-4124 at 10 mg/kg plus progesterone). There was astatistically significant difference detected: the levels ofcorticosterone were lowered in animals treated with progesterone after21 days of treatment (p=0.029, Mann-Whitney Wilcoxon test, two-tailed).This effect was not verified in sera taken at sacrifice. No differencesin serum corticosterone were found between the progesterone and theCDB-4124 groups, the progesterone and the RU-486 groups, or the RU-486group and the CDB-4124 groups.

The relationship between serum cortisol and serum corticosterone in eachgroup was also examined. There was a strong positive linear correlationbetween the two for CDB-4124 at 20 mg/kg (r²=0.78), for CDB-4124 at 10mg/kg (r²=0.82), and for RU 486 (r²=0.85). Adding progesterone to thefirst two CDB-4124 groups made the relationship far less strong (r²=0.34for Group 10 and r²=0.37 for Group 11, respectively). Progesteroneitself showed no such positive relationship (r²=−1.0). The control groupdemonstrated no relationship between the two glucocorticoids (r²=0.064).Thus, increased levels of cortisol in groups receiving CDB-4124 arecorrelated to levels of corticosterone, due perhaps to conversion fromcorticosterone that is somehow enhanced. This is consistent with aneffect of CDB-4124 seen above: an effect on metabolic enzymesresponsible for levels of progesterone and cortisol.

Although no strong effect of CDB-4124 on the primary glucocorticoid ofthe rat was found, nevertheless, for safety reasons, patients givenCDB-4124 or CDB-4059 in Phase I clinical trials should be monitored forpossible anti-glucocorticoid effects including a possible increase inserum cortisol, corticosterone, or ACTH.

Example 5 Testing Anti-Proliferative Effects of SPRMs in Uterine Cells

Any uterine cell lines can be used. Proliferation is measured in 96-wellmicrotiter plates. 5×10³ cells are added to each well. Culture mediumand drug solutions are added to wells with a Perkin Elmer CetusPRO/PETTE. The culture medium is IMEM supplemented with 5% fetal bovineserum. Eight drug concentrations are tested, in duplicate, from 0.078 uMto 10 uM. Samples include tamoxifen alone and each of the compoundsdisclosed in the instant specification in combination with tamoxifen.

After a four-day incubation, the medium is replaced with fresh mediumcontaining drug, and after a total of seven days, the cell monolayersare fixed with trichloracetic acid and stained with sulforhodamine dye.Absorbances (492 nm) of the extracted dye solutions are measured with aTitertek Multiscan plate reader. Dose response curves (percent ofcontrol absorbances vs. drug concentrations) are constructed in order toestimate IC₅₀ values defined as the drug concentrations (micromolar)which inhibited 50% proliferation. IC₅₀ values are correlative with apotency of a tested drug in inhibiting cell proliferation and thereforeprovide information required to identify compounds suitable forpreventing hyperproliferation of the uterine cells.

Example 6 CDB-4124 Lowers Luteal Phase Progesterone in CynomolgusMonkeys

Cynomolgus monkeys (Macaca fascicularis) (n=14) were treated orally for36 weeks with CDB-4124 or RU-486 at 1.0 mg/kg/day or with placebo(control). Another group (n=14) received Lupron® IM once per month.Urinary progesterone levels were measured for each animal for one monthduring the middle of the study (weeks 14-17) and for the last month ofthe study (weeks 33-36). The results are presented below:

Decrease in luteal phase No decrease in luteal phase progesteroneprogesterone Controls 1 13 Lupron ® 13 1 RU 486 9 5 CDB-4124 8 6

Example 7 CDB-4124 Does Not Lower Follicular Phase Estrogen inCynomolgus Monkeys

Urinary estrogen levels were measured for each animal of Example 6 forone month during the middle of the study (weeks 14-17) and for the lastmonth of the study (weeks 33-36). The follicular phase results are basedon 35 baseline ovulating cycles. The results are presented below:

Mean Sd Lower? Follicular Phase 68.3 19.6 Controls Week 18 81.5 27.4 NoWeek 36 86.3 23.8 No Lupron ® Week 18 49.9 19.3 Yes Week 36 41.7 13.4Yes RU 486 Week 18 67.4 27.1 No Week 36 64.8 30.0 No CDB-4124 Week 1863.8 24.6 No Week 36 67.3 22.9 No

Example 8 CDB-4124 and Lupron® but not RU 486 Suppress Proliferation inCynomolgus Monkey Endometrial Epithelia

At week 36, three animals from each group of Example 6 were injectedwithin 24 hours of sacrifice with the thymidine analog bromodeoxyuridine(BrdU), a marker of proliferating cells and their progeny, to assesstissue proliferation. Full thickness uterine sections were stained andexamined microscopically for evidence of proliferation in terms of the %cells positive for incorporation of BrdU:

Uterus epithelium Uterus stroma Breast TXT Brdu-% Brdu-% Brdu-% Control10.0 ± 2.5 2.6 ± 0.6 2.4 ± 1.1 Lupron ®  3.1 ± 0.8 2.2 ± 1.0 0.3 ± 0.1RU 486 12.6 ± 1.8 3.1 ± 1.0 0.9 ± 0.3 CDB-4124  2.1 ± 2.2  1.1 ± 0.251.9 ± 0.7

Example 9 CDB-4124 and RU 486 but not Lupron® Enhance Apoptosis inCynomolgus Monkey Endometrial Epithelium

Apoptosis was assessed in tissue from the same animals on slides by theterminal deoxynucleotidyl transferase mediated dUTP-biotin nick endlabeling (TUNEL) technique. The percent apoptotic cells is presentedbelow:

Uterus epithelium Uterus stroma Breast TXT Apo % Apo % Apo % Control 0.2± 0.1 0.7 ± 0.2 0.5 ± 0.3 Lupron 0.2 ± 0.1 0.2 ± 0.1 1.4 ± 0.7 RU 4860.5 ± 0.1 0.5 ± 0.1 1.2 ± 0.6 CDB-4124 0.5 ± 0.2 0.5 ± 0.1 2.6 ± 0.9

Example 10 Low Concentrations of CDB-4124 Increase Endometrial ThicknessDuring an Administration Period Beginning at Day 5 of a Female'sMenstrual Cycle

Thirty-nine pre-menopausal adult women diagnosed with endometriosis werethe subject of a six month study of Proellex™ (CDB-4124) in thetreatment of endometriosis. The study included three dose levels ofCDB-4124 as well as a positive control arm. The positive control wasLucrin®, a GnRH agonist, commonly used for the treatment ofendometriosis (also known as Lupron®). CDB-4124 was administered in adouble blinded fashion as a daily oral capsule at dosages of 12.5 mg/day(n=2), 25 mg/day (n=3) and 50 mg/day (n=3), beginning at day 5 of thewomen's menstrual cycle. Another group (n=4) were injected with a slowrelease formulation of Lucrin® once per month as a positive control.

All doses of CDB-4124, as well as the Lucrin® dose, on average reduceddistress related to pain over the course of the six month exposure tothe drug, with the 50 mg CDB-4124 dose reducing both the duration andintensity of pain more effectively than the 12.5 mg or 25 mg doses andis significantly better (p=0.0012) than Lucrin® in reducing the numberof days of pain over the course of the study. Pain reduction alsooccurred more rapidly than with the active control, Lucrin®. Theresponse of pain to treatment in this study was analyzed in two ways.Patients in the study maintained daily pain diaries to record theseverity and frequency of pain. In addition, at each office visit,patients filled out endometriosis symptom surveys that included aquestionnaire that evaluated intensity of pain on a bad day on a scaleof 0-10 with 10 being the greatest intensity. Daily pain diariesindicated that on average, women on Lucrin® experienced 19.4 days ofpain over the first three months. Women on 50 mg of CDB-4124 exhibitedless than 1 day of pain over the same period. Women on 25 mg and 12.5 mgof CDB-4124 exhibited more days of pain than that recorded by womenreceiving the highest dose of CDB-4124 or Lucrin®. There appeared to bea dose dependent effect on pain reduction. Over the 180 day treatmentperiod, pain diaries indicated that women on the 50 mg CDB-4124 dose had170 or 96% pain free days (standard deviation=8.86 days). This decreasein duration of pain was statistically better (p=0.0012) than the 117.8(74%; standard deviation 51.4 days) pain free days achieved withLucrin®. The 50 mg dose of CDB-4124 was also statistically superior toboth the 25 mg and the 12.5 mg doses with regard to pain free days.Patients on CDB-4124 12.5 mg and 25 mg doses had 115.9 (66%; standarddeviation 69.2 days) and 133.6 (75%; standard deviation 27.4 days) painfree days, respectively. These results clearly support a dose responsefor CDB-4124. The 25 mg and 12.5 mg doses of CDB-4124 were notstatistically different from Lucrin®. At the end of the first month oftherapy there was a statistically significant reduction in days of painin the 50 mg Proellex group (p=0.031) compared with baseline, but not inthe three other treatment groups. The intensity of pain was assessed bythe question: “On a scale of 1-10, with 0 being no pain and 10 beingextreme pain, how intense was your pain on a bad day?” The mean scoresfor intensity of pain at baseline were 6.3 for the CDB-4124 groups and6.1 for the Lucrin® group. Statistically significant relief from painwas evident by the first month in the 25 mg and 50 mg Proellex groups.At month three all four active treatment groups had statisticallysignificant reduction in pain compared with baseline, with the followingscores: 3.7 (p=0.03) for 12.5 mg CDB-4124, 3.2 (p=0.03) for 25 mgCDB-4124, 1.6 (p=0.015) for 50 mg CDB-4124 and 1.5 (p=0.016) forLucrin®. These dose related reductions continued until month six whenthe values for pain intensity were 2.0 (p=0.008), 2.8 (p=0.023), 0.6(p=0.004) and 0.7 (p=0.016), respectively. Two months after stoppingtreatment pain returned and was of similar intensity in all fourtreatment groups.

Women receiving Lucrin® in the study, on average, experienced areduction of estrogen to post-menopausal levels (<20 pg/ml) by monththree and this was maintained through month six of treatment. Thisoutcome was associated with a statistically significant increase(p=0.023) in biomarkers of bone resorption compared with the baselinevalues at month three, and therefore an increased risk of bone loss. Atmonth six as well as at the one-month follow up visit, this increase inmarkers of bone resporption was still present in women treated withLucrin®. All doses of CDB-4124 maintained estrogen concentrationssignificantly above those seen with Lucrin® and remained in the lownormal range (mean>40 pg/ml). Importantly, there were no significantchanges in biomarkers of bone resorption in any of the dose arms ofCDB-4124 at three and six months of treatment. Women withpost-menopausal levels of estrogen have been shown to be at greater riskfor bone loss and other medical conditions. Lucrin®, therefore, is notindicated for treatment lasting longer than six months.

Side effects of CDB-4124 were generally mild with no individual organsystem being involved systematically. Although this was a small studyand no definitive conclusions can be made from the safety data, therewas no single signal of safety observed.

Women in the study were closely monitored for changes in the structureof the endometrium. Data from these examinations suggest an inverse dosedependent effect of CDB-4124 on endometrial thickness, as measured byultrasound. Comparisons were made to both baseline and visit oneultrasound measurements of endometrial thickness. The clinical datashowed that progressive endometrial thickening occurs with all threedoses of CDB-4124. The endometrial thickening was most prominent withthe 12.5 mg dose and less so with the 25 mg and 50 mg doses. After sixmonths of treatment, the 12.5 mg dose resulted in a statisticallysignificant increase of 10.9 mm (p 0.016) in endometrial thickness frombaseline while the 25 mg and 50 mg doses showed a statisticallyinsignificant change of 9.8 mm and 3.9 mm respectively.

Four subjects who experienced significant bleeding in the study all hadan endometrial thickness of more than 20 mm and had been on treatmentfor 5 months or longer. In a separate study, women with uterine fibroidswere administered daily doses of 12.5 mg, 25 mg or 50 mg CDB-4124 for athree month period, beginning at day 5 of each woman's menstrual cycle.None of the subjects receiving the 12.5 mg or 25 mg doses had asignificant bleeding episode and their mean endometrial thicknessmeasurements were less than 20 mm. These data suggest that the risk ofbleeding is related to both duration of therapy and increasedendometrial thickness.

Example 11 Endometrial Biopsies of Women in the CDB-4124 TreatmentGroups

Endometrial biopsies were taken from 27 women exposed to 12.5 mg, 25 mgor 50 mg CDB-4124 for six months and 31 women with uterine fibroidsexposed to 12.5 or 25 mg CDB-4124 for three months. Specimens wereevaluated in a treatment blinded fashion utilizing the WHO diagnosticschema (Silverberg et al., tumors of the uterine corpus: epithelialtumors and related lesions. Tavassoli F A, Stratton M R, reditors. WHOClassification of Tumors: Pathology and Genetics of Tumors of the Breastand Female Genital Organs. Lyon, France: IARC Press, 2003: 221-232). Aconsensus primary end point result was determined for each specimen bymajority (two or more of three pathologists agree), or in the event ofall pathologists disagreeing the “worst” diagnosis of the three wasassigned. Additional findings were recorded using a structured datacollection instrument. All raw data was provided to the reviewingpathologists, who undertook an independent analysis that was the basisfor their conclusions.

The results demonstrated a consensus primary diagnosis in all CDB-4124treated subjects of benign endometrium, without any hyperplasias,endometrial intraepithelial neoplasia, or carcinomas. Thus, CDB-4124suppressed endometrial proliferation at every concentration tested. Theresults for the primary diagnosis were no different between the subjectswith endometriosis or uterine fibroids or the subjects exposed for threeor six months or among the three different doses.

Additional secondary findings within the “benign” category were noted,the most prominent being the presence of cystic dilation of glandssimilar to the histological pattern recently described for women treatedwith other progesterone receptor modulators such as asoprisnil,mifepristone and CDB-2914. The glandular epithelium within these cystsvaried in appearance, but contained non-physiologic combinations ofpoorly developed secretory activity, dying cells (apoptotic bodies) andrare mitoses. Other cystic glands were lined by inactive epithelium.Rare glandular mitoses seen at low doses of CDB-4124 disappeared at 50mg, suggesting an antiproliferative benefit with increasing dose. Thisconstellation of cysts and epithelial findings are novel and fall withinthe spectrum of progesterone receptor modulator associated endometrialchanges recently described for other compounds in this class. CDB-4124did not induce, however, the blood vessel wall thickening and latticedcapillary patterns seen with some other progesterone receptormodulators.

Importantly, across all treatment doses, a positive correlation wasobserved between increased endometrial thickness as measured byultrasound and the diagnosis of cystic glands by the reviewingpathologists. However, in females receiving the lowest doses ofCDB-4124, cystic glands were more prominent in number and size than infemales receiving the highest dose. There was a clear trend in the 12.5mg group for increasing thickness and more cysts between the 3 and 6months time points. This association of endometrial thickness withhistologic cysts, which becomes stronger with increasing duration oftherapy, suggests that the thickening of the endometrium is due to thedevelopment of glandular dilatation. Importantly, administration ofCDB-4124 to each treatment group began on day 5 of the females'menstrual cycle and consequently, no menstruation occurred in females ofany of the treatment groups until the drug was removed.

It is known that extensive glandularization of the endometrial bedbegins to occur soon after day 5. See FIG. 3. Vascularization andfurther glandular activity is hastened under the influence ofprogesterone starting around day 14. Without wishing to be bound bytheory, it is believed that, in contrast to females in the 50 mgtreatment group, CDB-4124 has not accumulated in females in the 12.5 mgand 25 mg treatment groups to a concentration sufficient to completelyblock progesterone during the females' first cycle, causing the cysticglands to swell in size and number under the influence of residual(unblocked) progesterone stores.

Administration of CDB-4124 beginning at a time point during the lutealphase (i.e., day 14 or thereafter) of a female's menstrual cycle willallow the female to menstruate during the initial cycle. It is expectedthat any early forming cystic glands will be shed during this menses,after which CDB-4124 concentrations are expected to be sufficiently highto block progesterone and thereby inhibit progesterone's vascular andglandular effects on the endometrium. Accordingly, the instant inventionprovides a dosing regimen for treatment of, inter alia,estrogen-dependent conditions comprising the administration ofrelatively low concentrations of progesterone antagonists such asCDB-4124, without unwanted thickening and increased friability of theendometrium. Thus, the presently disclosed dosing regimen provides theadvantage of reducing or eliminating, for example, breakthrough bleedingthat accompanies thickened, friable endometria, without the need forinducing periodic menstruations during progesterone antagonisttreatment. It is expected that beneficial results will also be obtained(to a relatively lesser extent) where higher concentrations of CDB-4124are administered for a period beginning during the luteal phase of thefemale's menstrual cycle. Thus, where, e.g. 50 mg of CDB-4124 areadministered for a period beginning at a time point in the luteal phaseof a female's menstrual cycle, further reductions in endometrialthickness are expected relative to those observed in the 50 mg treatmentgroup of Example 10 (for whom the administration period began at day 5of each female's menstrual cycle).

Example 12 Administration of Low Concentrations of a ProgesteroneAntagonist for Treating Endometriosis

Females suffering from endometriosis are divided into two groups: afirst group receives 12.5 mg of CDB-4124 for a six-month periodbeginning at day 5 of each female's menstrual cycle; a second groupreceives 12.5 mg of CDB-4124 for a six-month period beginning at day 15of each female's menstrual cycle. Endometrial thickness is monitoredregularly throughout the six-month period. Females in the second groupexhibit a lesser degree of endometrial thickening than those in thefirst group and preferably an absence of endometrial thickening whilebenefiting from reduced endometrial-induced pain.

I claim:
 1. A method for treating an estrogen dependent conditionselected from the group consisting of endometriosis and uterine fibroidscomprising intermittent administration of a composition comprising aselective progesterone receptor modulator (SPRM) at a dose of 12.5 mg to25 mg to a female in need thereof, said intermittent administrationcomprising administering said composition daily or every other day for aperiod of at least 30 days beginning during the luteal phase of saidfemale's menstrual cycle, then discontinuing said administration bymeans of a continual lack of treatment for a period of days sufficientto allow the female to menstruate then administering the compositiondaily or every other day for a period of at least 30 days, thendiscontinuing said administration b means of a continual lack oftreatment for a period of days sufficient to allow the female tomenstruate, and repeating this pattern of administration anddiscontinuance of administration for as long as necessary to achievetreatment of said conditions.
 2. The method of claim 1, wherein theestrogen dependent condition is endometriosis.
 3. The method of claim 1,wherein treatment is initiated at from day 14 to day 25 of said female'smenstrual cycle.
 4. The method of claim 1, wherein the SPRM is acompound of formula (I):

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein: X represents an alkyl, alkenyl, alkynyl, hydrogen, halogen,monoalkylamino or dialkylamino; R₁ represents ═O, ═NOH or ═NO-methyl; R₂represents a hydrogen or acetyl; and R₃ represents methyloxy, formyloxy,acetoxy, acyloxy, S-alkoxy, acetylthio, glycinate, vinyl ether,acetoxymethyl, methyl carbonate, halogens, methyl, hydroxy, or ethyloxy.5. The method of claim 4, wherein said compound is CDB-4124.
 6. Themethod of claim 4, wherein said compound is administered at a dosage of12.5 mg per day.
 7. The method of claim 4, wherein said compound isadministered at a dosage of 25 mg per day.
 8. The method of claim 5,wherein said compound is administered at a dosage of 12.5 mg per day. 9.The method of claim 5, wherein said compound is administered at a dosageof 25 mg per day.
 10. The method of claim 1, wherein said compound isadministered for a period of at least six months.
 11. The method ofclaim 1, wherein the SPRM is17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-dien-3,20-dione.12. The method of claim 1, wherein said intermittent administrationcomprises administering said composition daily or every other day for aperiod of four months beginning during the luteal phase of said female'smenstrual cycle, then discontinuing said administration by means of acontinual lack of treatment for a period of days sufficient to allow thefemale to menstruate then administering the composition daily or everyother day for a period of four months, then discontinuing saidadministration by means of a continual lack of treatment for a period ofdays sufficient to allow the female to menstruate, and repeating thispattern of administration and discontinuance of administration for aslong as necessary to achieve treatment of said conditions.